The most common form of heart disease is myocardial ischemia, which is characterized by an insufficient supply of blood, substrates and oxygen to the heart due to coronary artery obstruction. If not treated, irreversible damage ensues in the form of myocardial infarction (heart attack). The overall aim of the Project is to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which will be accomplished by utilizing an integrative approach including cellular and molecular studies as well as integrative whole animal physiology. Project 1 involves the study of the mechanisms of cardiac protection in the second window of ischemic protection (SWOP) in chronically instrumented conscious swine. One unique aspect of this Project is the use of the large mammalian model, which resembles pathophysiology in humans more closely than rodents, lacks preformed coronary collateral vessels, and the heart is sufficiently large to provide measurements of regional function, blood flow, biochemistry, molecular biology and pathology from the same animals in both the ischemic zone and a contralateral, remote, non-ischemic zone. The project is based, in part, on the novel observation that either regional cardiac denervation or adrenergic receptor blockade abrogates the second window of protection. There are three major hypotheses: A)SWOP is critically dependent on the sympathetic nervous system;B)Regional cardiac denervation alters SWOP in the remote, non-ischemic zone;C)SWOP results in enhanced long chain fatty acid (LCFA) oxidation during ischemia, potentially due to AMP kinase elevation, an effect which is abolished following SWOP in conscious pigs with regional cardiac denervation. Project 1 is tied closely to the other projects and cores, as well as to the major themes of the Program Project, which are: 1)Mechanisms of myocardial ischemia and reperfusion; 2)Molecular signaling;3)Myocardial protection and cell survival vs. cell death;4)lntegrative cardiovascular research. This project is also linked closely to Project 2, which also studies the chronically instrumented swine model, but in Project 2 the model is one of repetitive stunning (myocardial hibernation). Indeed, several of the aims are shared by Projects 1 and 2, since the two projects will address several of the same questions in the two different models. Project 1 interacts with Project 3 in terms of molecular signaling and mechanisms of apoptosis, and with Project 4 particularly related to H11 kinase, which will be administered to pigs with regional cardiac denervation, to determine if H11 kinase can restore protection after cardiac denervation. Project 1 also utilizes all of the Cores.